Our laboratory has had a long-standing interest in renal cell cancer (RCC). This highly vascular tumor is known to contain a mutation in the Von-Hippel Lindau (VHL)tumor suppressor gene in over 80% of clear cell carcinomas, and this is linked to deregulation of vascular endothelial growth factor (VEGF), a potent angiogenic agent. More recently, our laboratory identified FGF-5 as an RCC-expressed antigen recognized by T-cells, but not expressed on normal adult tissues. FGF-5 is also a potent angiogenic agent as well as a transforming growth factor overproduced by several different types of adenocarcinomas. We are current beginning a new initiative directed at identifying the mediators of angiogenesis and growth of RCC, and neutralizing these biological activities in preclinical tumor models and in patients with RCC. In preclinical models of RCC xenografts in nude mice, we are evaluating neutralizing antibodies to FGF-5. RCC was found to express FGF-5 when expression screening of a cDNA library from a RCC line (by immune recognition by a cytotoxic T-lymphocyte reactive with the autologous RCC tumor line) revealed FGF-5 as the targeted RCC-associated tumor antigen. This molecule, originally identified by its ability to transform 3T3, is expressed in approximately 60% of RCC lines and some prostate and breast cancer lines. Others have found it expressed in bladder cancer and pancreatic cancer, where it demonstrates autocrine and paracrine growth-promoting activies as well. We have not found it expressed by normal adult tissues by RT-PCR, and it therefore represent an excellent therapeutic target for multiple adenocarcinomas including RCC.Parallel to these laboratory studies, we are conducting clinical protocols of anti-angiogenic agents. In a new, accruing clinical protocol, we are evaluating the efficacy of a humanized neutralizing antibody to hVEGF (Genentech, Inc) in a randomized, double-blind, placebo-controlled format in patients with progressive, metastatic RCC. In this 150 patient trial, we are also evaluating the use of novel non-invasive imaging techniques to evaluate anti-angiogenic agents in clinical trials. The next generation of clinical studies will be combinations of agents if the anti-VEGF monoclonal antibody demonstrates any significant clinical activity.